The enigmatic megakaryocyte gradually reveals its secrets

The recent cloning of thrombopoietin has brought many insights into the cellular and molecular mechanisms of megakaryocyte and platelet development. Thrombopoietin was cloned based on its binding to the product of the proto-oncogene c-mpl and was found to affect all aspects of thrombopoiesis. Many of the molecular pathways that mediate thrombopoietin action have been discerned. Upon hormone binding, the megakaryocyte thrombopoietin receptor homodimerizes, activating members of the JAK family of kinases which, in turn, phosphorylate the receptor, generating docking sites for second messengers that affect multiple signalling pathways. Ultimately, cellular proliferative and anti-apoptotic mechanisms are initiated, increasing megakaryocyte numbers, as are processes that uncouple DNA synthesis from nuclear and cytoplasmic division generating polyploid cells. As the net result of thrombopoietin action is an expansion of cells that give rise to mature platelets, the availability of the recombinant hormone has provided new opportunities to manipulate blood cell development for therapeutic benefit.